6- And 6,6-disubstituted-3-substituted amino-1-azabicyclo-[3.2.0]hept-2-en-7-one-2-carboxylic acid

ABSTRACT

Disclosed are 6- and 6,6-disubstituted-3-substituted amino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acids (I): ##STR1## wherein R 1  and R 2  are, inter alia, independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, aryl, and aralkyl; and R&#39; and R&#34; are independently selected from the group consisting of: H, substituted and unsubstituted alkyl and aralkyl, or together form a substituted or unsubstituted cyclic group. 
     Such compounds and their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds and methods of treatment comprising administering compounds and compositions when an antibiotic effect is indicated.

BACKGROUND OF THE INVENTION

This is a continuation, of application Ser. No. 176,818 filed Aug. 8,1980, now abandoned; which in turn is a continuation-in-part of Ser. No.119,914, filed Feb. 8, 1980, now abandoned; which in turn is acontinuation application of Ser. No. 843,379, filed Oct. 19, 1977, nowabandoned.

This invention relates to 6- and 6,6-disubstituted-3-substitutedamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acids and theirpharmaceutically acceptable salt, ester and amide derivatives (I) whichare useful as antibiotics: ##STR2## wherein: R¹ and R² are independentlyselected from the group consisting of hydrogen (R¹ and R² are not bothhydrogen), substituted and unsubstituted: alkyl, alkenyl, and alkynyl,having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, andalkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6carbon atoms in the alyl moieties; aryl, such as phenyl; aralkyl,aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and thelinear chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl,heterocyclyl and heterocyclylalkyl wherein the substituent orsubstituents relative to the above-named radicals are selected from thegroup consisting of: amino, mono, di- and trialkylamino, hydroxyl,alkoxyl, mercapto, alkylthio, arylthio such as phenylthio, sulfamoyl,amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; andwherein the hetero atom or atoms in the above-named heterocyclicmoieties are selected from the group consisting of 1-4 oxygen, nitrogenor sulphur atoms; and wherein the alkyl moieties of the above-recitedsubstituents have 1-6 carbon atoms; and

R' and R" are independently selected from hydrogen; substituted orunsubstituted: alkyl and cycloalkyl having from 1-10 carbon atoms,aralkyl, such as phenylalkyl and heterocyclylalkyl wherein the alkyl has1-6 carbon atoms and the hetero atom or atoms are selected from O, N andS, and cyclic group wherein R' and R" are joined; and wherein the ringor chain substituent or substituents on R', R" or the cyclic radicalformed by their joinder are selected from the group consisting of amino,mono-, di- and trialkylamino (each alkyl having from 1-6 carbon atoms),hydroxyl, carboxyl, alkoxyl having from 1-6 carbon atoms, halo such aschloro, bromo and fluoro, nitro, --SO₂ NH₂, phenyl, benzyl, andalkoxylcarbonyl having 1-3 carbon atoms in the alkoxyl moiety.

This invention also realtes to carboxylate derivatives of I which arealso antibiotics and which may be represented by the following genericstructure (I): ##STR3## wherein X' is oxygen, sulphur or NR' (R'=H orloweralkyl having 1-6 carbon atoms); and R^(3') is, inter alia,representatively selected from the group consisting of hydrogen,conventional blocking groups such as trialkylsilyl, acyl and thepharmaceutically acceptable salt, ester and amide moieties known in thebicyclic β-lactam antibiotic art; the definition of R^(3') is given ingreater detail below.

This invention also relates to processes for the preparation of suchcompounds (I); pharmaceutical compositions comprising such compounds;and to methods of treatment comprising administering such compounds andcompositions when an antibiotic effect is indicated.

There is a continuing need for new antibiotics. For unfortunately, thereis no static effectiveness of any given antibiotic because continuedwide scale usage selectively gives rise to resistant strains ofpathogens. In addition, the known antibiotics suffer from thedisadvantage of being effective only against certain types ofmicroorganisms. Accordingly the search for new antibiotics continues.

Thus, it is an object of the present invention to provide a novel classof antibiotics which are useful in animal and human therapy and ininanimate systems. These antibiotics are active against a broad range ofpathogens which representatively include both gram positive bacteriasuch as S. aureus, Strep. pyogenes. B. subtilis and gram negativebacteria such as E. coli, Proteus morganii, Pseudomonas, Serratia andKlebsiella. Further objects of this invention are to provide chemicalprocesses for the preparation of such antibiotics and their non-toxicpharmaceutically acceptable salts; pharmaceutical compositionscomprising such antibiotics; and to provide methods of treatmentcomprising administering such antibiotics and compositions when anantibiotic effect is indicated.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are conveniently prepared by thefollowing scheme: ##STR4## In words relative to the above reactiondiagram, the compounds of the present invention may be prepared from thestarting material 1. This starting material is disclosed and claimed incommonly assigned U.S. patent application Ser. No. 160,719 filed June18, 1980, which is incorporated herein by reference. The 3-substituentin the starting material is a leaving group preferably selected fromchloro, bromo, --OMs (methylsulfonyloxy), or --OTs(p-toluylsulfonyloxy). The radicals X' and R^(3') of the startingmaterial 1 are as defined above for the compounds of the presentinvention, (structure I, above). The compounds of the present inventionmay be prepared, as shown by the above scheme, essentially by treatingstarting material 1, wherein X is the above-described leaving group,with a primary or secondary amine, H₂ NR' or HNR'R", respectively. Thereaction is conducted in a solvent such as ethanol (EtOH), dioxane,dimethylformamide (DMF), hexamethylphosphoramide (HMPA), and the like ata temperature of from 0° to 50° C. for from 1 to 24 hours.

Relative to the generic representation of the compounds of the presentinvention, preferred representative values for the 3-substituent --NR'R"are: ##STR5##

As mentioned above, the compounds of the present invention may beprepared as pharmaceutically acceptable carboxyl derivatives. Such formsmay be established on the starting material 1, or X' may be oxygen andR^(3') may be any readily removable blocking group such as benzyl,p-nitrobenzyl, o-nitrobenzyl and the like. Removal of such blockinggroups is conveniently effected by hydrolysis or hydrogenation. Thus,when the carboxyl blocking group benzyl is employed, the most convenientdeblocking procedure is hydrogenation at 1 to 4 atmospheres H₂ pressureat 25° C. in a solvent such as EtOH, EtOAc, dioxane, H₂ O, or the likein the presence of a catalyst such as Pd, Pd/C, or PtO₂.

Alternatively, the radical X'R^(3') may be established after the abovereaction scheme, if desired, and may have the identities disclosed inthe above-cited, concurrently filed incorporated by reference U.S.patent application Ser. No. 160,719 filed June 18, 1980.

Identification of the Radical --COX'R^(3')

In the generic representation of the compounds of the present invention(I, above), the radical represented by --COX'R^(3') is, inter alia,--COOH (X' is oxygen and R^(3') is hydrogen) and all radicals known tobe effective as pharmaceutically acceptable ester, anhydride (R^(3') isacyl) and amide radicals in the bicyclic β-lactam antibiotic art, suchas the cephalosporins and penicillins and the nuclear analogues thereof.

Suitable radicals (R^(3')) include conventional protecting or carboxylblocking groups. The term "blocking group" as utilized herein isemployed in the same manner and in accordance with the teaching of U.S.Pat. No. 3,697,515 which is incorporated herein by reference.Pharmaceutically acceptable derivatives of the present invention fallingin this class are given below. Suitable blocking esters thus includethose selected from the following list which is representative and notintended to be an exhaustive list of possible ester groups, wherein X'=Oand R^(3') is given:

(i) R^(3') =CR^(a) R^(b) R^(c) wherein at least one of R^(a), R^(b) andR^(c) is an electron-donor, e.g., p-methoxyphenyl,2,4,6-trimethylphenyl, 9-anthryl, methoxy, CH₂ SCH₃, tetrahydrofur-2-yl,tetrahydropyran-2-yl or fur-2-yl. The remaining R^(a), R^(b) and R^(c)groups may be hydrogen or organic substituting groups. Suitable estergroups of this type include p-methoxybenzyloxycarbonyl and2,4,6-trimethylbenzyloxycarbonyl.

(ii) R^(3') =CR^(a) R^(b) R^(c) wherein at least one of R^(a), R^(b) andR^(c) is an electron-attracting group, e.g., benzoyl, p-nitrophenyl,4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl,ethoxycarbonylmethyl, arylsulphonylmethyl, 2-dimethylsulphoniummethyl,o-nitrophenyl or cyano. Suitable esters of this type includebenzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and2,2,2-tribromoethoxycarbonyl.

(iii) R^(3') =CR^(a) R^(b) R^(c) wherein at least two of R^(a), R^(b)and R^(c) are hydrocarbon such as alkyl, e.g., methyl or ethyl, or aryl,e.g. phenyl and the remaining R^(a), R^(b) and R^(c) group, if there isone, is hydrogen. Suitable esters of this type includet-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl andtriphenylmethoxycarbonyl.

(iv) R^(3') =R^(d), wherein R^(d) is adamantyl, 2-benzyloxyphenyl,4-methylthiophenyl or tetrahydropyran-2-yl.

Silyl esters, under this category of blocking groups, may convenientlybe prepared from a halosilane or a silazane of the formula: R⁴ ₃ SiX';R⁴ ₂ SiX'₂ ; R⁴ ₃ Si.NR⁴ ₂ ; R⁴ ₃ Si.NH.COR⁴ ; R⁴ ₃ Si.NH.CO.NH.SiR⁴ ₃ ;R⁴ NH.CO.NH⁴.SiR⁴ ₃ ; or R⁴ C(OSiR⁴ ₃); HN(SiR⁴ ₃)₂ wherein X' is ahalogen such as chloro or bromo and the various groups R⁴, which can bethe same or different, represent hydrogen atoms or alkyl, e.g., methyl,ethyl, n-propyl, iso-propyl; aryl, e.g., phenyl; or aralkyl, e.g.,benzyl groups.

More generally stated, pharmaceutically acceptable carboxyl derivativesof the present invention are those derived by reacting I with alcohols,phenols, mercaptans, thiophenols, acylating reagents and the like. Forexample, esters and amides of interest are the above-listed startingmaterials and final products having the following group at the2-position of the thienamycin nucleus: --COX'R^(3') wherein X' isoxygen, sulfur, or NR' (R' is H or R^(3')), and R^(3') is alkyl having1-10 carbon atoms, straight or branched, such as methyl, ethyl, t-butyl,pentyl, decyl and the like; carbonylmethyl, including phenacyl,p-bromophenacyl, p-t-butylphenacyl, acetoxyacetylmethyl,pivaloxyacetylmethyl, carboxymethyl, and its alkyl and aryl esters,α-carboxy-α-isopropyl; aminoalkyl including 2-methylaminoethyl,2-diethylaminoethyl, 2-acetamidoethyl, phthalimidomethyl,succinimidomethyl; alkoxyalkyl wherein the alkoxy portion has 1-10 andpreferably 1-6 carbon atoms; but can be branched, straight or cyclic,and the alkyl portion has 1-6 carbon atoms, such as methoxymethyl,ethoxymethyl, isopropoxymethyl, decyloxymethyl, ethoxypropyl,decyloxypentyl, cyclohexyloxymethyl and the like; alkanoyloxyalkylwherein the alkanoyloxy portion is straight or branched and has 1-6carbon atoms and the alkyl portion has 16 carbon atoms, such asacetoxymethyl, pivaloyloxymethyl, acetoxymethyl, propionyloxyethyl,acetoxypropyl, and the like; haloalkyl wherein halo is chloro, bromo,fluoro, or iodo, and the alkyl portion is straight or branched having1-6 carbon atoms, e.e., 2,2,2-trichloroethyl, trifluoroethyl,2-bromopropyl, diiodomethyl, 2-chloroethyl, 2-bromoethyl, and the like;alkenyl having 1-10 carbon atoms, either straight or branched, e.g.,allyl, 2-propenyl, 3-butenyl, 4-butenyl, 4-pentenyl, 2-butenyl,3-pentenyl, 3-methyl-3-butenyl, metallyl, 1,4-cyclohexadien-1-yl-methyl,and the like alkynyl having 1-10 carbon atoms, either straight orbranched e.g., 3-pentenyl, propargyl, ethynyl, 3-butyn-1-yl, and thelike; alkanoyl, either straight or branched, having 1-10 carbon atoms,such as pivaloyl, acetyl, propionyl, and the like; aralkyl orheteroaralkyl wherein alkyl has 1-3 carbon atoms, and hetero means 1-4hetero atoms being selected from the group consisting of O, S, or N,such as benzyl, benzhydryl, and substituted benzyl, benzhydryl, or e.g.,benzyl or benzhydryl substituted with 1-3 substituents such as benzyl,phenoxy, halo, loweralkyl, loweralkanoyloxy of 1-5 carbon atoms, loweralkoxy, hydroxy, nitro, blocked carboxy, or combinations thereof, e.g.,p-chlorobenzyl, o-nitrobenzyl, 3,5-dinitrobenzyl, p-methoxybenzyl,m-benzoylbenzyl, p-t-butylbenzyl, m-phenoxybenzyl, p-benzoylbenzyl,p-nitrobenzyl, 3,5-dichloro-4-hydroxybenzyl, p-methoxycarbonylbenzyl,p-methoxybenzhydryl, p-carboxybenzyl, the latter being either the freeacid, ester or the sodium salt, 2,4,6-trimethylbenzyl,p-pivaloyloxybenzyl, p-t-butoxycarbonyl benzyl, p-methylbenzyl,p-benzoyloxybenzyl, p-acetoxybenzyl, p-2-ethylhexanoylbenzyl,p-ethoxycarbonylbenzyl, p-benzoylthiobenzyl, p-benzamidobenzyl,o-pivaloyloxybenzyl, m-pivaloyloxybenzyl, p-isopropoxybenzyl,p-t-butoxybenzyl, as well as the cyclic analogues thereof,2,2-dimethyl-5-coumaranmethyl, 5-indanylmethyl, p-trimethylsilylbenzyl,3,5-bis-t-butoxy-4-hydroxybenzyl; 2-thienylmethyl, 2-furylmethyl,3-t-butyl-5-isothiazolmethyl, 6-pivaloyloxy-3-pyridazinylethyl,5-phenylthio-1-tetrazolylmethyl, or the like (the use of the terms loweralkyl or lower alkoxy in this context means 1-4 carbon atoms chain); orphthalidyl; or phenylethyl, 2-(p-methylphenyl)ethyl, and thearylthioalkyl analogues, aryloxyalkyl wherein aryl is preferably aphenyl ring ahving 0-3 substituents preferably 0 or 1 substituents inthe ortho or para positions and alkyl is 1-6 carbon atoms, e.g.,(4-methoxy)phenoxymethyl, phenoxymethyl, (4-chloro)phenoxymethyl,(4-nitro)phenoxymethyl, (4-benzyloxy)phenoxymethyl,(4-methyl)phenoxymethyl, (4-benzyloxy)phenoxymethyl,(4-methyl)phenoxymethyl, (2-methoxy)phenoxymethyl, (1-phenoxy)ethyl,(4-amino)phenoxymethyl, (4-methoxy)phenylthiomethyl,(4-chloro)phenylthiomethyl, phenylthioethyl; aryl wherein aryl isphenyl, 5-indanyl, or substituted phenyl having 0-3 substituents,preferably 0 or 1 substituents in the ortho or para position, e.g.,(4-methyl)phenyl, (4-hydroxy)phenyl, (4-t-butyl)phenyl, p-nitrophenyl,3,5-dinitrophenyl, or p-carboxyphenyl, the latter having either the freeacid or the sodium salt form; aralkenyl wherein aryl is phenyl andalkenyl has 1-6 carbon atoms, such as 3-phenyl-2-propenyl; aralkoxyalkylwherein aralkoxy is benzyloxy, and alkyl has 1-3 carbon atoms, such asbenzyloxymethyl, (4-nitro)benzyloxymethyl, (4-chloro)benzyloxymethyl;alkylthioalkyl wherein the alkylthio portion has 1-10 and preferably 1-6carbon atoms, but can be branched, straight or cyclic, and the alkylportion has 1-6 carbon atoms, such as methylthioethyl, ethylthioethyl,cyclohexylthiomethyl, decylthiobutyl, methylthiopropyl,isopropylthioethyl, methylthiobutyl and the like.

In addition to the esters (and thio esters) listed above, amides arealso embraced by the present invention, i.e., wherein X' is the ##STR6##group. Representative of such amides are those wherein R' is selectedfrom the group consisting of hydrogen, methyl, ethyl, phenyl,p-methoxyphenyl, benzyl, carboxymethyl, methylthioethyl, and heteroaryl;also embraced by --COX'R^(3') are anhydrides wherein R^(3') is acyl, forexample, benzyloxycarbonyl, ethoxycarbonyl, benzoyl, and pivaloyl.

The most preferred --COX'R^(3') radicals of the present invention arethose wherein (relative to Structure IIa above X' is oxygen, sulphur orNR' (R' is selected from the group consisting of hydrogen and loweralkyl); and R^(3') is selected from the group consisting of: loweralkyl,lower alkenyl, such as methallyl, 3-methylbutenyl, 3-butenyl, and thelike; methylthioethyl; benzyl and substituted benzyl such asp-t-butylbenzyl, m-phenoxybenzyl, p-pivaloyloxybenzyl, p-nitrobenzyl andthe like; pivaloyloxymethyl, 3-phthalidyl and acetoxymethyl,propionyloxymethyl, acetylthiomethyl, pivaloylthiomethyl, allyl,4-butenyl, 2-butenyl, 3-methyl-2-butenyl, phenacyl, acetoxyacetylmethyl,methoxymethyl, p-acetoxybenzyl, p-pivaloyloxybenzyl, p-isopropoxybenzyl,5-indanylmethyl, 5-indanyl, benzyloxymethyl, ethylthioethyl,methylthiopropyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,dimethylaminoacetoxymethyl, crotonolacton-3-yl, and acetamidomethyl.

Relative to the generic expression of the compounds of the presentinvention (Ia): ##STR7## The radical X'R^(3') may be established aftersynthesis, rather than being established on starting material 1, byoperating upon the carboxyl group. Ester embodiments are convenientlyprepared by conventional procedures known in the art. Such proceduresinclude:

1. Reaction of I in free acid form with a diazoalkane such asdiazomethane, phenyldiazomethane, diphenyldiazomethane and the like inan inert solvent such as dioxane, THF, halohydrocarbons, acetonitrile,ethylacetate, and the like at a temperature of from -78° C. to 25° C.for from a few minutes to 2 hours.

2. Reaction of the metallic salts (e.g., Na, Li) of the acid (I) with anactivated alkyl halide such as methyliodide, benzylbrommide, orm-phenoxybenzylbromide, p-t-butylbenzylbromide, m-phenoxybenzylbromide,and the like. Suitable reaction conditions include inert, anhydrouspolar non-protic solvents such as hexamethylphosphoramide, DMF, THF,dioxane, and the like at a temperature of from -78° C. to 25° C. forfrom a few minutes to 4 hours.

3. Reaction of the free acid (I) with an alcohol such as methanol,ethanol, benzyl alcohol, and the like. This reaction may be conducted inthe presence of a carbodiimide condensing agent such asdicyclohexylcarbodiimide or the like. Suitable solvents, at atemperature of from 0°0 C. to reflux for from 15 minutes to 18 hours,include CHCl₃, CH₃ CH, CH₂ Cl₂ and the like.

4. Reaction of an acid anhydride of I prepared by reacting the free acid(I) with an acid chloride such as ethylchloroformate,benzylchloroformate and the like, with an acid such as those listed in3. under the same conditions of reaction as given above for 3. Theanhydride is prepared by reaction I and the acid chloride in a solventsuch as tetrahydrofuran (THF), CH₂ Cl₂ and the like at a temperature offrom 25° C. to reflux for from 15 minutes to 10 hours.

5. Reaction of labile esters of I such as the trimethylsilyl ester,dimethyl-t-butylsilyl ester or the like with RX' wherein X' is halogensuch as bromo and chloro and R is as defined in a solvent such as THF,CH₂ Cl₂ and the like at a temperature of from 0° C. to reflux for from15 minutes to 16 hours.

The amides of the present invention are most conveniently prepared byreacting the acid anhydride of I with ammonia or with the amine ofchoice, e.g., the alkyl-, dialkyl-, aralkyl- or heterocyclic amineslisted above.

The above-reacted schemes of esterification are well-known in therelated bicyclic β-lactam antibiotic art and indeed in all of generalorganic synthesis as and it is to be noted that there is no unduecriticality of reaction parameters in the preparation of the compoundsof the present invention.

The above-recited schemes of esterification are well known in therelated bicyclic β-lactam antibiotic art and indeed in all of generalorganic synthesis and it is to be noted that there is no unduecriticality of reaction parameters in the preparation of the compoundsof the present invention.

The products of this invention (I) form a wide variety ofphamacologically acceptable salts with inorganic and organic bases;these include, for example, metal salts derived from alkali metal oralkaline earth metal hydroxides, carbonates or bicarbonates and saltsderived from primary, secondary or tertiary amines such asmonoalkylamines, dialkylamines, trialkylamines, lower alkanolamines,di-lower-alkanolamines, lower alkylenediamines, N-N-diaralkyl loweralkylenediamines, aralkylamines, amino substituted lower alkanols,N,N-di-lower alkylamino substituted lower alkanols, amino-, polyamino-and guanidino-substituted lower alkanoic acids and nitrogen containingheterocyclic amines.

Representative of such salts are sodium, potassium, and calcium salts,and amine salts such as benzylhydrylamine, N-benzyl-2-phenethylamine,N,N'-dibenzylethylenediamine, and procaine salts.

The salts of this invention are pharmacologically acceptable non-toxicderivatives which can be used as the active ingredient in suitable unitdosage pharmaceutical forms. Also, they may be combined with other drugsto provide compositions having a broad spectrum of activity.

The novel compounds are valuable antibiotics active against variousgram-positive and gram-negative bacteria and, accordingly, find utilityin human and veterinary medicine. The compounds of this invention cantherefore be used as antibacterial drugs for treating infections causedby gram-positive or gram-negative bacteria, for example, againstStaphylococcus aureus, Escherichia coli, Klebsiella pneamoniae,Serratia, Salmonella typhosa, Pseudomonas and Bacterium proteus. Theantibacterials of the invention may further be utilized as additives toanimal feeding stuffs, for preserving foodstuffs and as disinfectants.For example, they may be employed in aqueous compositions inconcentrations ranging from 0.1 to 100 parts of antibiotic per millionparts of solution in order to destroy and inhibit the growth of harmfulbacteria on medical and dental equipment and as bactericides inindustrial applications, for example, in waterbased paints and in thewhite water of paper mills to inhibit the growth of harmful bacteria.

The products of this invention may be used alone or in combination as anactive ingredient in any one of a variety of pharmaceuticalpreparations. These antibiotics and their corresponding salts may beemployed in capsule form or as tablets, powders or liquid solutions oras suspensions or elixirs. They may be adminstered orally, intravenouslyor intramuscularly.

The compositions are preferably presented in a form suitable forabsorption of the gastro-intestinal tract. Tablets and capsules for oraladministration may be in unit dose presentation form, and may containconventional excipients such as binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillersfor example, lactose, sugar, maizestarch, calcium phosphate, sorbitol orglycine; lubricants, for example, magnesium stearate, talc, polyethyleneglycol, silica; disintegrants, for example, potato starch or acceptablewetting agents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in the art. Oral liquid preparations maybe in the form of aqueous or oily suspension, solution, emulsions,syrups, elixirs, etc. or may be presented as a dry product, forreconstitution with water or other suitable vehicles before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example, sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils, forexample almond oil, fractionated coconut oil, oily esters, propyleneglycol, or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoates or sorbic acid. Suppositories will containconventional suppository bases, e.g. cocoa butter or other glyceride.

Compositions for injection may be presented in unit dose form inampules, or in multidose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form for reconstitution with asuitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compositions may also be prepared in suitable forms for absorptionthrough the mucous membranes of the nose and throat or bronchial tissuesand may conveniently take the form of powder or liquid sprays orinhalants, lozenges, throat paints, etc. For medication of the eyes orears, the preparations may be presented as individual capsules, inliquid or semi-solid form, or may be used as drops etc. Topicalapplications may be formulated in hydrophobic or hydrophilic bases orointments, creams, lotions, paints, powders, etc.

Also, in addition to a carrier, the instant compositions may includeother ingredients such as stabilizers, binders, antioxidants,preservatives, lubricators, suspending agents, viscosity agents orflavoring agents and the like. In addition, there may also be includedin the composition other active ingredients to provide a broaderspectrum of antibiotic activity.

For veterinary medicine the composition may, for example, be formulatedas an intramammary preparation in either long or quick-release bases.

The dosage to be administered depends to a large extent upon thecondition of the subject being treated and the weight of the host, theroute and frequency of administration, the parenteral route beingpreferred for generalized infections and the oral route for intestinalinfections. In general, a daily oral dosage consists of from about 2 toabout 600 mg. of active ingredient per kg. of body weight of the subjectin one or more applications per day. A preferred daily dosage for adulthumans lies in the range of from about 15 to 150 mg. of activeingredient per kg. of body weight.

The instant compositions may be administered in several unit dosageforms as, for example, in solid or liquid orally ingestible dosage form.The compositions per unit dosage, whether liquid or solid may containfrom 0.1% to 99% of active material, the preferred range being fromabout 10-60%. The composition will generally contain from about 15 mg.to about 1500 mg. of the active ingredient; however, in general, it ispreferable to employ a dosage amount in the range of from about 100 mg.to 1000 mg. In parenteral administration the unit dosage is usually thepure compound in a slightly acidified sterile water solution or in theform of a soluble powder intended for solution.

The following Examples, illustrate but do not limit the product,process, compositional or method of treatment aspects of the presentinvention. All temperatures are given in °C.

EXAMPLE 1 Preparation of 4-(2-Acetoxyethyl)-azetidin-2-one ##STR8##

A mixture of 4-(2-acetoxyvinyl)-azetidin-2-one (3.00 g), 10% Pd/C (0.15g) and ethylacetate (EtOAc) (120 ml) is hydrogenated in a 500 ml glassbomb on a Parr shaker at an initial pressure of 39 psi. After shaking 10mins (final pressure of 20 psi), the mixture is filtered through a padof MgSO₄ to remove the catalyst. The filtrate is concentrated in vacuoand the residue stripped with anhydrous benzene to provide4-(2-acetoxyethyl)-azetidin-2-one (3.098 g) as a clear oil: ir(neat)3.01, 5.66, 5.75, 7.28, 8.05, and 9.61 cm⁻¹ ; nmr(CDCl₃)δ 1.95 (m, 2),2.07 (s,3), 2.60 (m, 1), 3.12 (m, 1), 3.70 (m, 1), 4.15 (m, 2), and 6.77(br s, 1).

EXAMPLE 2 Preparation ofN-(t-Butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one ##STR9##

Triethylamine (Et₃ N) (2.96 ml, 21.2 mmol) and t-butyldimethylsilylchloride (3.059 g, 20.3 mmol) are added to an ice-cold stirring solutionof 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g, 19.3 mmol) in anhydrousdimethylformamide (DMF) (20 ml). A white precipitate appearsimmediately. The cooling bath is removed and the mixture is stirred at25° C. (room temperature) for 5 mins. The mixture is diluted withbenzene (200 ml), washed with H₂ O (5×80 ml) and brine, dired withMgSO₄, filtered, and evaporated under reduced pressure to affordN-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (5.078 g) asan off white solid: ir(neat) 5.75, 8.08, 8.41, 11.92, and 12.18 cm⁻¹ ;nmr (CDCl₃) δ0.25 (s, 6), 0.98 (s, 9), 1.97 (m, 2), 2.05 (s, 3), 2.67(dd, 1), 3.20 (dd, 1) 3.62 (m, 1), and 4.12 (t,2); mass spectrum m/e 214(M⁺ -57) and 172.

EXAMPLE 3 Preparation ofN-(t-Butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin-2-one ##STR10##

A solution of N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one(41.7 g, 0.154 mol) in anhydrous methanol (415 ml) is stirred under a N₂atmosphere with ice-bath cooling. A solution of sodium methoxide (415mg, 7.7 mmol) in anhydrous methanol (15 ml) is added and the resultingsolution is stirred in the cold for 2 more hrs. Acetic acid (2.2 ml) isthen added and the solvents are evaporated in vacuo (i.v.). The residueis taken up in EtOAc (300 ml), washed with H₂ O (4×75 ml), 5% NaHCO₃ (75ml) and brine, dried with MgSO₄ and evaporated i.v. to a clear oil (21.3g). This material is purified by chromatography on a Baker silica gelcolumn (425 g, packed under EtOAc). After a 100 ml forefraction, 25 mlEtOAc fractions are collected every 2.5 mins. Fractions 41-49 yieldstarting material and fractions 51-90 affordN-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin- 2-one (19.4 g) asa clear oil: ir (neat) 2.88, 5.73, 5.80, 7.52, 7.67, 7.99, 8.40, 11.95,and 12.18 cm⁻¹ ; nmr (CDCl₃)δ 0.25 (s, 6), 0.98 (s, 9), 1.82 (m, 2),2.67 (dd, 1), 3.17 (dd, 1), 3.67 (t, 2), and 3.67 (m,1); mass spectrumm/e 172.

EXAMPLE 4 Preparation ofN-(t-Butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one ##STR11##

Anhydrous chromium trioxide (CrO₃) (1.94 g, 19.4 mmol) is added to asolution of anhydrous pyridine (3.07 g, 38.8 mmole) in anhydrousmethylene chloride (CH₂ Cl₂) (50 ml). The resulting mixture is stirredat room temperature for 15 mins. A solution ofN-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin-2-one (0.74 g, 3.23mmol) in anhydrous CH₂ Cl₂ (5 ml) is added all at once. After stirringat room temperature for 5 mins, the mixture is decanted and the dark,gummy residue is washed with more CH₂ Cl₂. The combined CH₂ Cl₂supernatant is evaporated i.v. The residue is tabken up in diethyl etherand filtered to remove chromium salts. The ethereal filtrate is washedwith 5% NaHCO₃, 5% HCl, 5% NaHCO₃ and brine, dried with MgSO₄, filtered,and evaporated i.v. to yieldN-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.54 g) as anoff-white solid: ir(CHCl₃) 5.77, 5.80, 7.36, 7.60, 7.99, 8.50 and 11.95cm⁻¹ ; nmr (CDCl₃)δ 0.23(s, 3), 0.27 (s, 3), 0.98 (s, 9), 2.63 (ddd, 1),2.65 (dd, 1), 3.07 (ddd, 1), 3.37 (dd), 3.97 (m, 1), and 9.78 (t, 1);mass spectrum m/e 170 and 128.

EXAMPLE 5 Preparation ofN-(t-Butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one##STR12##

To a flame dried, 50 ml, 3-neck flask fitted with a N₂ inlet, magneticstirrer, addition funnel, and serum cap are added anhydroustetrahydrofuran (THF) (10.5 ml) and diisopropyl amine (0.579 ml, 4.13mmol). The solution is cooled in an ice-methanol bath under N₂ andtreated with 2.4N n-butyl lithium in hexane (1.72 ml). After beingstirred at -10° for 15 mins, the solution is cooled to -78° and treateddropwise over 9 mins with a solution of benzyl acetate (0.620 g, 4.13mmol) in anhydrous THF (3.5 ml). After stirring 15 more mins at -78° C.the reaction mixture is treated dropwise over 13 mins with a solution ofN-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.894 g, 3.93mmol) in anhydrous THF (6 ml). The reaction mixture is stirred at -78°an additional 15 mins and then quenched with 2.5N HCl (6 ml). EtOAc (100ml) is added and the oragnic phase is separated, washed with H₂ O (2×20ml), 5% NaHCO₃ (20 ml) and brine, dried with MgSO₄, and filtered. Thefiltrate is evaporated i.v. and the residue stripped with φH to yieldN-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one(1.432 g) as an oil: ir (neat) 2.87, 5.73, 5.79, 7.57, 7.96, 8.39,11.92, and 12.16 cm⁻¹ ; mass spectrum m/e 362, 320, 278, 170 and 128.

EXAMPLE 6 Preparation ofN-(t-Butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one##STR13##

Anhydrous CrO₃ (2.274 g, 22.74 mmol) is added to a solution of anhydrouspyridine (3.597 g, 45.48 mmol) in anhydrous CH₂ Cl₂ (60 ml). Afterstirring at room temperature (25° C.) for 15 mins, the reaction mixtureis treated all at once with a solution ofN-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one(1.432 g, 3.79 mmol) in anhydrous CH₂ Cl₂ (25 ml). The resulting mixtureis stirred at 25° C. for 5 mins. The CH₂ Cl₂ layer is decanted from thedark, gummy residue which is triturated with more CH₂ Cl₂. The combinedCH₂ Cl₂ phase is evaporated i.v. The residue is triturated withdiethylether (Et₂ O) (100 ml) in several portions and the Et₂ O extractsare filtered to remove chromium salts. The ethereal filtrate is washedwith 5% NaHCO₃, 1N HCl, 5% NaHCO₃ and brine, dried with MgSO₄, filtered,and evaporated i.v. to yieldN-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one(1.042 g) as a pale yellow oil: ir (neat) 5.72 (3 poorly resolvedpeaks), 7.59 7.98, 8.42, and 11.93 cm⁻¹ ; nmr (CDCl₃)δ 0.18 (s, 3), 0.22(s, 3), 0.97 (s, 9), 2.53 (dd, 1), 2.63 (dd, 1), 3.13 (dd, 1), 3.28 (dd,1), 3.47 (s,2), 3.88 (m, 1), 5.17 (s, 2), and 7.33 (s, 5); mass spectrumm/e 360, 318, and 2.76.

EXAMPLE 7 Preparation of4-(3-Benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one ##STR14##

N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one(302 mg, 0.80 mmol) is dissolved in acetic acid (4.0 ml) and thesolution is diluted with H₂ O (2.0 ml). The resulting solution isstirred in a securely stoppered, 10 ml, round-bottom flask in an oilbath maintained at 73° C. for 7 hrs. After cooling to room temperature,the reaction mixture is diluted with EtOAc and toluene and evaporatedi.v. The residue is stripped twice with toluene to yield a yellow oil(220 mg). The crude product is chromatographed on Baker silica gel (8.8g, packed under EtOAc). The column is eluted with EtOAc; 3 ml fractionsbeing collected every 2.25 mins. Fractions 14-30 are combined andevaporated i.v. to provide4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (114 mg) as a clearoil: ir (neat) 3.04, 5.68, 5.72 and 5.83 cm⁻¹ ; nmr (CDCl₃)δ 2.52 (ddd,1), 2.67 (dd, 1), 3.02 (dd, 1), 3.12 (ddd, 1), 3.48 (s, 2), 3.88 (m, 1),5.18 (s, 2), 6.17 (m, 1), and 7.37 (s, 5); mass spectrum m/e 261 (M⁺),233, 219, 192, 127 and 91.

EXAMPLE 8 Preparation of4-(3-Benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2one ##STR15##

Freshly recrystallized p-carboxy benzene sulfonylazide (241 mg, 1.06mmol) is added to a solution of4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (276 mg, 1.06 mmol)in anhydrous acetonitrile (6.6 ml). The resulting suspension is cooledin an ice-bath and stirred while Et₃ N (443 μl, 3.18 mmol) is added. Theresulting yellow solution is stirred at room temperature. A precipitateforms quickly. After 90 mins, the mixture is diluted with EtOAc (50 ml)and filtered. The filtrate is washed with H₂ O (2×10 ml), 0.5N NaOH(2×10 ml), H₂ O (4×10 ml) and brine, dried with MgSO₄, filtered, andevaporated i.v. to an off-white solid (273 mg). This is triturated withEt₂ O to provide4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one (227 mg) as acream colored powder: ir (film from CHCl₃) 3.0, 4.65, 5.66, 5.82, 6.05,7.21, 7.70 and 8.23 cm⁻ 1 ; nmr (CDCl₃)δ 2.63 (ddd,1), 2.97 (dd, 1),3.15 (ddd, 1), 3.40(dd, 1), 3.98 (m, 1), 5.27 (s, 2), 6.13 (m, 1), and7.38 (s, 5); mass spectrum m/e 259, 245, 231, and 218.

EXAMPLE 9 Preparation of Benzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate ##STR16##

A solution of 4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one(20 mg) in anhydrous benzene (5 ml) is irradiated for 60 mins at roomtemperature using a Hanovia 450 W medium-pressure mercury lamp and aPyrex filter. Dry N₂ is bubbled through the solution prior to and duringthe photolysis. Evaporation of the solvent in vacuo gives an oil (17 mg)which is purified by chromatography on a 250μ×20×20 cm silica gel GFplate using 3:1 φH--EtOAc as developing solvent. The band at Rf 0.3 isremoved and eluted with EtOAc to give a clear oil (2.4 mg). Thismaterial is further purified by tlc on a 250μ×7.5×8.5 cm silica gel GFplate. The cleanly resolved band at Rf 0.29 is removed and eluted withEtOAc to give benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate(0.7 mg) as a clear oil: ir (CCl₄) 1783, 1773, and 1744 cm⁻ 1 ; ir(CHCl₃) 1767, 1741 cm⁻¹ ; uv (Cy) 215 nm; nmr (CDCl₃)δ 2.36 (dd, J=8 and18.5, 1), 2.90 (dd, J=6 and 18.5, 1), 2.92 (dd, J=2 and 16, 1), 3.63(dd,J=5 and 16, 1), 4.11 (m, 1), 4.71 (s, 1), 5.19 (s, 2) and 7.33 (s, 5);mass spectrum m/e 259 (M⁺), 231 (M⁺ -28), 217 (M⁺ -42), 203, 187, 186,168 (M⁺ -91), 124, and 91; high resolution mass spectrum m/e 259.0842(C₁₄ H₁₃ NO₄).

EXAMPLE 10 Preparation of Benzyl3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate ##STR17##

Benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (26 mg, 0.1mmol) in anhydrous DMF (0.5 ml) containing PCl₃ (27 mg, 0.2 mmol) iskept at 25° C. for 5 hrs. The mixture is diluted with toluene (5 ml),washed with H₂ O (5×1 ml) 5% HCl (2 ml), 5% NaHCO₃ (2 ml) and brine,dried with MgSO₄, and filtered. Evaporation of the solvent in vacuoprovides crude benzyl3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 11 Preparation of Benzyl3toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR18##

p-Toluenesulfonic anhydride (33 mg, 0.1 mmol) and Et₃ N (17 μl, 0.12mmol) are added to a solution of benzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (26 mg., 0.1 mmol) inanhydrous CH₂ Cl₂ (2 ml). The resulting solution is stirred at roomtemperature for 2 hours. The mixture is diluted with CH₂ Cl₂ (10 ml),washed with H₂ O (2×5 ml), pH 3 phosphate buffer (5 ml) and 5% NaHCO₃ (5ml), dried with MgSO₄, filtered and evarporated i.v. to provide benzyl3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 12 Preparation of Benzyl6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR19##

A solution of benzyl3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(41 mg) in anhydrous THF (0.5 ml) is added dropwise over 5 mins to astirring solution of lithium diisopropylamide (from 15.5 μl ofdiisopropylamine and 70 μl of 1.6N BuLi) in anhydrous THF (1.5 ml) at-78°. The resulting solution is stirred under a N₂ atm at -78° for 10mins and then trifluoroacetaldehyde (50 mg) is added all at once. After1 more min, saturated aqueous NH₄ Cl solution (1.5 ml) is added and themixture is allowed to warm to room temperature. The mixture is dilutedwith EtOAc (20 ml), washed with water and brine, dried with MgSO₄,filtered, and evaporated in vacuo. The benzyl6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 13 Preparation of Benzyl6-(3-phenyl-1-hydroxypropyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-oxo-2-carboxylate##STR20##

The procedure of Example 12 is duplicated except that3-phenylpropionaldehyde (67 mg) is substituted for trifluoroacetaldehydeto provide benzyl6-(3-phenyl-1-hydroxypropyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 14 Preparation of Benzyl6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR21##

A solution of benzyl3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (56 mg) inanhydrous THF (0.5 ml) is added dropwise over a few minutes to astirring solution of lithium diisopropylamide (from 31 μldiisopropylamine and 140 μl 1.6N BuLi) in anhydrous THF (3 ml) at -78°.After 15 more mins at -78°, the solution is treated with methyliodide(125 μl) and then allowed to warm to -20° over a period of 30 mins.Saturated aqueous NH₄ Cl (3 ml) is added and the mixture is allowed tocome to room temperature. The mixture is diluted with EtOAc (50 ml),washed with pH 3 phosphate buffer, water, 5% NaHCO₃, and brine, driedwith magnesium sulfate, and evaporated in vacuo to give benzyl6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 15 Preparation of Benzyl6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR22##

Benzyl6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate isconverted to its enolate derivative with lithium diisopropylamide inanhydrous THF at -78° as described in the previous example. To thissolution is added 10 equivalents of acetaldehyde. Workup as described inexample 12 yields benzyl6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 16 Preparation of Benzyl6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR23##

Morpholine (17.5 μl) is added to an ice-cold, stirring solution ofbenzyl6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(51 mg) in anhydrous DMF (0.5 ml). The resulting solution is allowed towarm to room temperature (25° C.) and then stirred at room temperaturefor 4 hrs. Ethylacetate (10 ml) is added and the solution is washed withwater (5×2 ml), pH 3 phosphate buffer, 5% NaHCO₃, brine, dried withMgSO₄, and filtered. Evaporation of the solvent in vacuo leaves benzyl6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 17 Preparation of Sodium6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR24##

A mixture of benzyl6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(25 mg), 10% palladium on powdered charcoal (25 mg), sodium bicarbonate(5 mg), dioxane (2 ml), and water (1 ml) is hydrogenated at 40 psi for30 mins. The mixture is filtered to remove the catalyst which is washedwith water (3×3 ml). The combined filtrate is extracted with ethylacetate (2×2 ml), concentrated in vacuo, and lyophilized to give sodium6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 18 Preparation of Benzyl6-(3-phenyl-1-hydroxypropyl)-3-[N-methyl-N(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR25##

A mixture of benzyl6-(3-phenyl-1-hydroxypropyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(55 mg), N-methyl-N-(2-dimethylaminoethyl)amine (10.2 mg), andtriethylamine (28 μl) in anhydrous DMF (0.5 ml) is stirred at roomtemperature for 4 hrs. The mixture is diluted with ethyl acetate (10ml), washed with water (5×2 ml), and brine, dried with MgSO₄, filteredand evaporated in vacuo to provide benzyl6-(3-phenyl-1-hydroxypropyl)-3-[N-methyl-N(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 19 Preparation of6-(3-phenyl-1-hydroxypropyl)-3-[N-methyl-N-(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylicacid ##STR26##

A mixture of benzyl6-(3-phenyl-1-hydroxypropyl)-3-[N-methyl-N-(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(25 mg), 10% palladium on powdered charcoal (25 mg), dioxane (3 ml),water (1.5 ml), and ethanol (0.5 ml) is hydrogenated at 45 psi for 1 hr.The catalyst is filtered off and washed with water (5 ml). The combinedfiltrate is extracted with ethyl acetate, concentrated in vacuo to ca. 1ml, and lyophilized to afford6-(3-phenyl-1-hydroxypropyl)-3-[N-methyl-N-(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylicacid.

EXAMPLE 20 Preparation of Benzyl6-(1-hydroxyethyl)-6-methyl-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR27##

A solution of benzyl6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(50 mg) in anhydrous DMF (1 ml) is cooled in an ice-bath and stirredwhile triethylamine (28 μl) and propylamine (12.4 μl) are added. Theresulting solution is allowed to slowly warm to room temperature andkept at room temperature for 1 hr. The solution is diluted wiht ethylacetate (10 ml), washed with water (5×2 ml), pH 3 phosphate buffer (2ml), 5% NaHCO₃ (2 ml), and brine, dried with MgSO₄, filtered, andevaporated in vacuo to give benzyl6-(1-hydroxyethyl)-6-methyl-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.

EXAMPLE 21 Preparation of Sodium6-(1-hydroxyethyl)-6-methyl-3-propylamine-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR28##

Benzyl6-(1-hydroxyethyl)-6-methyl-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylateis hydrogenolyzed by the procedure of Example 17 to provide the titlecompound.

EXAMPLE 22

Following the foregoing examples and text there are prepared thefollowing compounds in an analgous manner:

    __________________________________________________________________________     ##STR29##                                                                    Com-                                                                          pound                                                                             R.sup.1  R.sup.2                                                                          R'         R"       R.sup.3'                                  __________________________________________________________________________    (1.)                                                                              H        H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                        (2.)                                                                              H        H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (3.)                                                                             H        H                                                                                 ##STR30## H        H                                          (4.)                                                                             H        H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                        (5.)                                                                              H        H  CH.sub.3   CH.sub.3 Na                                         (6.)                                                                             H        H  CH.sub.3                                                                                  ##STR31##                                                                             H                                         (7.)                                                                              H        H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (8.)                                                                              HOCH.sub.2                                                                             H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                        (9.)                                                                              HOCH.sub.2                                                                             H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (10.)                                                                            HOCH.sub.2                                                                             H                                                                                 ##STR32## H        H                                          (11.)                                                                            HOCH.sub.2                                                                             H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                        (12.)                                                                             HOCH.sub.2                                                                             H  CH.sub.3   CH.sub.3 Na                                         (13.)                                                                            HOCH.sub.2                                                                             H  CH.sub.3                                                                                  ##STR33##                                                                             H                                         (14.)                                                                             HOCH.sub.2                                                                             H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (15.)                                                                              ##STR34##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                         (16.)                                                                             ##STR35##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (17.)                                                                             ##STR36##                                                                             H                                                                                 ##STR37## H        H                                          (18.)                                                                             ##STR38##                                                                             H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                         (19.)                                                                             ##STR39##                                                                             H  CH.sub.3   CH.sub.3 Na                                         (20.)                                                                             ##STR40##                                                                             H  CH.sub.3                                                                                  ##STR41##                                                                             H                                         (21.)                                                                              ##STR42##  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (22.)                                                                              ##STR43##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                         (23.)                                                                             ##STR44##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (24.)                                                                             ##STR45##                                                                             H                                                                                 ##STR46## H        H                                          (25.)                                                                             ##STR47##                                                                             H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                         (26.)                                                                             ##STR48##                                                                             H  CH.sub.3   CH.sub.3 Na                                         (27.)                                                                             ##STR49##                                                                             H  CH.sub.3                                                                                  ##STR50##                                                                             H                                         (28.)                                                                              ##STR51##                                                                             H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (29.)                                                                              ##STR52##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                         (30.)                                                                             ##STR53##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (31.)                                                                             ##STR54##                                                                             H                                                                                 ##STR55## H        H                                          (32.)                                                                             ##STR56##                                                                             H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                         (33.)                                                                             ##STR57##                                                                             H  CH.sub.3   CH.sub.3 Na                                         (34.)                                                                             ##STR58##                                                                             H  CH.sub.3                                                                                  ##STR59##                                                                             H                                         (35.)                                                                              ##STR60##                                                                             H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (36.)                                                                              ##STR61##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                         (37.)                                                                             ##STR62##                                                                             H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (38.)                                                                             ##STR63##                                                                             H                                                                                 ##STR64## H        H                                          (39.)                                                                             ##STR65##                                                                             H  CH.sub.2 CH.sub. 2 OH                                                                    H        Na                                         (40.)                                                                             ##STR66##                                                                             H  CH.sub.3   CH.sub.3 Na                                         (41.)                                                                             ##STR67##                                                                             H  CH.sub.3                                                                                  ##STR68##                                                                             H                                         (42.)                                                                              ##STR69##                                                                             H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (43.)                                                                             CH.sub.3 H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                        (44.)                                                                             CH.sub.3 H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (45.)                                                                            CH.sub.3 H                                                                                 ##STR70## H        H                                          (46.)                                                                            CH.sub.3 H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                        (47.)                                                                             CH.sub.3 H  CH.sub.3   CH.sub.3 Na                                         (48.)                                                                            CH.sub.3 H  CH.sub.3                                                                                  ##STR71##                                                                             H                                         (49.)                                                                             CH.sub.3 H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                         (50.)                                                                            CH.sub.3 CH.sub.2                                                                      H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                        (51.)                                                                             CH.sub.3 CH.sub.2                                                                      H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (52.)                                                                            CH.sub.3 CH.sub.2                                                                      H                                                                                 ##STR72## H                                                   (53.)                                                                            CH.sub.3 CH.sub.2                                                                      H  CH.sub.2 CH.sub.2 OH                                                                     H        H                                         (54.)                                                                             CH.sub.3 CH.sub.2                                                                      H  CH.sub.3   CH.sub.3 Na                                         (55.)                                                                            CH.sub.3 CH.sub.2                                                                      H  CH.sub.3                                                                                  ##STR73##                                                                             Na                                        (56.)                                                                             CH.sub.3 CH.sub.2                                                                      H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (57.)                                                                            φCH.sub.2                                                                           H  CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                        (58.)                                                                            φCH.sub.2                                                                           H  CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (59.)                                                                           φCH.sub.2                                                                           H                                                                                 ##STR74## H        H                                          (60.)                                                                           φCH.sub.2                                                                           H  CH.sub.2 CH.sub.2 OH                                                                     H        Na                                        (61.)                                                                            φCH.sub.2                                                                           H  CH.sub.3   CH.sub.3 Na                                         (62.)                                                                           φCH.sub.2                                                                           H  CH.sub.3                                                                                  ##STR75##                                                                             Na                                        (63.)                                                                             φCH.sub.2                                                                          H  CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        (64.)                                                                              ##STR76##                                                                             CH.sub.3                                                                         CH.sub.2 CH.sub.2 CH.sub.3                                                               H        Na                                         (65.)                                                                             ##STR77##                                                                             CH.sub.3                                                                         CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                             H        H                                          (66.)                                                                             ##STR78##                                                                             CH.sub.3                                                                          ##STR79## H        H                                          (67.)                                                                             ##STR80##                                                                             CH.sub.3                                                                         CH.sub.2 CH.sub.2 OH                                                                     H        Na                                         (68)                                                                              ##STR81##                                                                             CH.sub.3                                                                         CH.sub.3   CH.sub.3 Na                                         (69.)                                                                             ##STR82##                                                                             CH.sub.3                                                                         CH.sub.3                                                                                  ##STR83##                                                                             H                                                         CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                              Na                                        __________________________________________________________________________

EXAMPLE 23 Benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate##STR84##

A mixture of 4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one(718 mg. 2.5 mMol), rhodium (II) acetate (5 mg) and anhydrous benzene(50 ml) is deoxygenated by bubbling nitrogen through it for 45 minutes.The mixture is then stirred and heated in an oil bath maintained at 80°C. for 70 minutes. After cooling to room temperature, the mixture isfiltered and the filtrate is evaporated under vacuum to an oil.Crystallization from ethyl acetate (5 ml)-diethylether (20 ml) providesbenzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (502 mg, 77%yield) as small, white prisms: mp 100°-102°; IR (CH₂ Cl₂) 1770; 1741cm⁻¹ ; UV (dioxane) 220 nm; NMR (CDCl₃, 300 MHz) α 2.43 (dd,1,J=8 and19, H4a), 2.94 (dd,1,J=6.5 and 19, H4b), 2.99 (dd,1,J=2 and 16, H6B),3.63 (dd,1,J=5 and 16, H6α), 4.18 (m,1,H5), 4.76 (S,1,H2), 5.23 (S,2,CH₂φ), and 7.40 (S,5,ArH); MS m/e 259 (M+), 231 (M+-28), 217 (M+-42), 203,187, 186, 168 (M+-91), 124, and 91.

Anal. Calculated for C₁₄ H₁₃ NO₄ : C, 64.86; H, 5.05; N, 5.40. Found: C,64.92; H, 5.01; N, 5.11.

EXAMPLE 24 Dicyclohexylammonium1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate ##STR85##

A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate(25.9 mg, 0.1 mMol) in dioxane (1.5 ml) is added to a mixture of 10%palladium on charcoal (5 mg) and dioxane (1.0 ml) which had beenequilibrated under an atmosphere of hydrogen for 10 minutes. Theresulting mixture is stirred under 1 atmosphere of hydrogen at roomtemperature for 30 mins., during which time 2.6 ml of hydrogen areabsorbed. The mixture is filtered and the catalyst is washed with moredioxane (0.5 ml). The filtrate, which contains1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylic acid, is divided intotwo equal 1.5 ml portions.

One portion of the dioxane filtrate is treated with a solution ofdicyclohexylamine (9.1 mg, 0.05 mMol) in dioxane. The solvent is removedunder vacuum and the residue is triturated with diethyl ether to yielddicyclohexylammonium 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylateas a white powder: IR (Nujol) 1764, 1637 cm⁻¹ ; NMP (D₂ O) α 1.1-2.2(m,-CH₂ CH₂ CH₂ CH₂ CH₂ -), 2.64 (dd,J=7.8 and 19.0, H4a), 2.89 (dd,J=7.9 and 19.0, H4b), 3.08 (dd, J=2 and 16.6, H6β), 3.26 (m, N-CH), 3.61(dd, J=4.7 and 16.6, H6α), 4.17 (m, H5), and 4.8 (br s, HOD, obscures H2resonance).

EXAMPLE 25 Benzyl3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-2n-7-one-2-carboxylate##STR86##

p-Toluenesulfonic anhydride (326 mg, 1 muol ) andN,N-diisopropylethylamine (192 μl, 1.1 muol) are added to an ice-cold,stirring solution of benzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 muol) inanhydrous methylene chloride (10 ml). The resulting solution is stirredin the cold and under a nitrogen atmosphere for 2.5 hours. The solutionis diluted with methylene chloride (20 ml), washed with water (10 ml),1M pH3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10ml) dried with magnesium sulfate, filtered, and evaporated under vacuumto a semi-solid. This material is triturated with ice-cold ethyl acetate(2×2 ml) and diethyl ether (2×5 ml) to provide benzyl3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(276 mg, 67%) as a white powder. Recrystallization from methylenechloride-diethyl ether gives analytically pure product as small whiteneedles: mp 103°- 105°; IR (CH₂ Cl₂) 1786, 1723, 1382, and 1190 cm⁻¹ ;NMR (CDCl₃) 8 2.44 (s,3,ArCh₃) 3.03 (dd,1,J=3.0 and 17.0, HGβ), 3.16(dd,1,J=8.5 and 18.7,H4a), 3.32 (dd,1,J=10.0 and 18.7,H46), 3.55(dd,1,J=5.5 and 17.0, HG), 4.21 (m,1,H5), 5.14 (ABq,2,J=12,CH₂ Ar), 7.35(S,5,ArHO, 7.26 and 7.75 (two d's,4,J=9,ArH); UV(dioxane) 283 (E6600)and 277 (E6500) nm.

Anal., Calculated for C₂₁ H₁₉ NO₆ S: C, 61.01; H, 4.63; N, 3.39. Found:C, 59.94; H, 4.47; N, 3.26.

EXAMPLE 26 Benzyl3-(p-nitrobenzenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR87##

An ice-cold solution of benzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (20 mg, 0.077 mmol) inmethylene chloride (2 ml) is treated with p-nitrobenzenesulfonicanhydride (37.3 mg, 0.096 mmol) and N,N-diisopropylethylamine (18.3 μl,0.015 mmol). After stirring in the cold for 20 minutes, the solution isdiluted with cold methylene chloride (1 ml) and cold 0.1M pH 7 phosphatebuffer (2 ml) and shaken. The organic phase is separated, washed withcold 0.1M pH 7 phosphate buffer (2×2 ml), water and brine, dried withmagnesium sulfate, and filtered. The filtrate is diluted with coldmethanol (0.5 ml) and quickly evaporated under vacuum to give a solid.The crude product is triturated with cold methanol and dried undervacuum to provide benzyl3-(p-nitrobenzenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate(26 mg) as a white solid: mp 86°-88°; IR (CH₂ Cl₂) 1794, 1723, 1521, and1344 cm⁻¹ ; UV (CHCl₃) 257 (ε 10,600) and 280 (ε 7,600) nm; NMR (CDCl₃)δ3.08 (dd, 1, J=3.6 and 17, H6β), 3.25 (dd, 1, J=8.8 and 18, H3a), 3.35(dd, 1, J=9.8 and 18, H4b), 3.59 (dd, 1, J=5.4 and 17, H6α),4.26(m,1,H5), 5.10 (ABq, 2, J=21.2, CH₂ φ), 7.32 (s, 5, C₆ H₅), 8.03 and8.22 (two d's, 4, J=9.3, NO₂ C₆ H₄).

Preparation of p-nitrobenzene sulfonic anhydride

A mixture of p-nitrobenzenesulfonic acid (20 g), phosphorous pentoxide(50 g) and 1,2-dichloroethylene (100 ml) is heated at reflux for 4 days.The hot supernatant is decanted from the gummy residue and allowed tocool to room temperature. The resulting crystalline precipitate ofp-nitrobenzenesulfonic anhydride (1.5 g) is collected, washed withanhydrous diethylether, and dried under vacuum. The gummy residue istwice more refluxed overnight with 100 ml portions of dichloroethyleneand worked up as above to provide additional p-nitrobenzenesulfonicanhydride (4.0 g): mp 171°-172° C.

EXAMPLE 27 Benzyl3-diphenylphosphoryl-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR88##

An ice-cold, stirring solution of benzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (13 mg, 0.05 mMol),4-dimethylamine pyridine (1.2 mg, 0.01 mMol) andN,N-diiscpropylethylamine (12.2 μl, 0.07 mMol) in anhydrous acetonitrile(0.5 ml) is treated with diphenyl chlorophosphate (12.4 μl, 0.06 mMol).The resulting solution is stirred in the cold and under a nitrogenatmosphere for 2 hours, then diluted with methylene chloride (5 ml),washed with water (2 ml), 0.1M pH 7 phosphate buffer (2 ml) and brine,dried ovr magnesium sulfate, and filtered. Evaporation of the filtrateunder vacuum leaves crude benzyl3-diphenylphosphoryl-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate(22 mg) as an oil: UV (dioxane) 281 nm; NMR(CDCl₃) α 2.90 (dd,1,J=3 and17, H6β),3.17(m,2,H4a and H4b), 3.52 (dd,1, J=5.5 and 17, H6α),4.13(m,1,H5), 5.28(S,2,CH₂ φ), and 7.30(m,15,ArH).

EXAMPLE 28N-(t-Butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one##STR89##

A mixture of crudeN-(t-butyldimethylsily)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one(11.33 g, 30 mmol), ethanol (300 ml) and 10% palladium on charcoal (1.13g) is hydrogenated at 50 psi for 1 hour. The mixture is filtered and thefiltrate is treated with water (150 ml) containing sodium bicarbonate(2.52 g, 30 mmol) and concentrated under vacuum to ca 100 ml. Theaqueous concentrate is washed with ethyl acetate (2×100 ml) andlyophilized to provide the sodium carboxylate (7.70 g) as a whitepowder.

The sodium salt and p-nitrobenzyl bromide (6.48 g, 30 mmol) aredissolved in anhydrous dimethyl formamide (150 ml) under a nitrogenatmosphere. After standing for 1 hour at room temperature, the solutionis evaporated under vacuum to a semi-solid. The residue is taken up inethyl acetate (200 ml), washed with water (2×200 ml) and brine, driedover magnesium sulfate, filtered, and evaporated under vacuum. Theresidual yellow oil is chromatographed on silica gel (250 g) using 1:1toluene-ethyl acetate as eluting solvent to provideN-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl)-azetidin-2-one(8.92 g, 70%) as an oil which solidified on standing: IR (CH₂ Cl₂) 3585,1733, 1527, and 1350 cm⁻¹ ; NMR(CDCl₃) 8 0.22 (s,3,CH₃), 0.25 (s,3,CH₃),0.93 (s,9,C(CH₃)₃), 1.16-2.33 (m,2,CH--CH₂ --CH), 2.40-3.47 (m,3,OH andH3 and H3β), 2.55 (d,2,J=6, CH₂ CO₂), 3.50-4.33 (m,2,H4 and CH--OH),5.30 (s,2,CH₂ Ar), and 7.55, 8.27 (two d's,4,J=8.5, ArH).

EXAMPLE 29N-(t-Butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbony)-2-hydroxypropyl]-azetidin-2-one##STR90##

A mixture of crudeN-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-Hydroxypropyl)-azetidin-2-one(13.46 g, 35.6 mmol), 10% palladium on charcoa, and ethanol (200 ml) ishydrogenated at 40 psi for 30 mins. The mixture is filtered and thefiltrate is evaporated under vacuum and stripped with toluene to giveN-(t-butyldimethylsilyl)-4-(3-carboxy-2-hydroxypropyl)-azetidin-2-one(9.51 g) as an off-white solid: IR (neat film from Me₂ CO) 3200 (br),1735, and 1700 (shifts to 1590 with Et₃ N) cm⁻¹ ; NMR (Me₂ CO-d₆) 8 0.25(s,6,2CH₃), 0.98 (s,9,C(CH₃)₃) 1.17-2.33 (m,2,CH--C CH₂ --CH), 2.50(d,2,J=6.5, CH₂ CO₂), 2.50-3.40 (m,2,H3 and H3β), 3.97 (m,2,H4 andCHOH); MS on bistrimethylsily derivative m/e 431 (M+), 416(M+-57) and332 (374-42).

The crude carboxylic acid is suspended in anhydrous acetonitrate (150ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) andtriethylamine (4.9 ml, 35 mμol). The resulting solution is kept at roomtemperature for 2 days and then in a refrigerator for 3 days. Thereddish orange solution is evaporated under vacuum and the residueshaken with ethyl acetate (100 ml, 2×50 ml) and filtered to removetriethylammonium bromide. The ethyl acetate filtrate is washed withwater (3×100 ml) and brine, dried with magnesium sulfate, filtered, andevaporated under vacuum to an amber oil (13.62 g). Crystallization fromdiethyl ether affordsN-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one(6.84 g) as an off-white powder. Chromatography of the mother liquors ona silica gel column using 1:1 toluene-ethyl acetate as eluting solventaffords addition product (3.14 g) as an oil which solidifies.

EXAMPLE 30N-(t-Butyldimethylsily)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one##STR91##

Anhydrous chromium trioxide (16.88 g 169 mmol) is added to a solution ofanhydrous pyridine (27.3 ml, 338 mmol) in anhydrous methylene chloride(470 ml). The resulting mixture is stirred at room temperature for 30minutes and then treated with a solution ofN-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one(8.92 g, 21.1 mmol) in methylene chloride (80 ml). The reaction mixtureis stirred an additional 15 minutes at room temperature and then treatedwith 2-propanol (6.75 ml). The methylene chloride paste is decanted fromthe dark, tary residue and evaporated under vacuum. The residue fromthis operation is triturated with diethyl ether (350 ml) and filteredthrough a pad of magnesium sulfate which is washed with additional ether(150 ml). The ethereal filtrate is washed with water (200 ml), 5%aqueous sodium bicarbonate (200 ml) and brine, dried with magnesiumsulfate, filtered, evaporated under vacuum, and stripped with toluene toafford the crude product (5.98) as an amber oil. Chromatigraphy on asilica gel column using 3:2 petroleum etherethyl acetate as elutingsolvent yieldsN-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one(5.17 g, 58%) as a pale yellow, viscous oil which solidifies.Trituration with diethyl ether gives the product as small, whitecrystals: mp 65°-66.5°, IR (CH₂ CL₂) 1732, 1522, and 1350 cm) NMR(CDCl₃) 8 0.20 (s,3,CH₃), 0.23 (s,3,CH₃), 0.93 (s,9,C(CH₃)₃), 2.58(dd,1,J=2.7 and 15.7, H3β), 2.72 (dd,1, J=9.4 and 18.2, CH₂ COCH₂ CO₂),3.19 (dd,1,J=4.0 and 18.2, CH₂ COCH₂ CO₂), 3.35 (dd,1,J=5.3 and15.7,H3α), 3.55 (s,2, COCH₂ CO₂), 3.90 (m,1,H4), 5.30 (s,2,CH₂ Ar), 7.55and 8.25 (two d¹⁵,4,J-8.5, ArH); MS m/e 405 (M⁺ -15), 363 (M⁺ -57), 321(363-42) and 136.

Anal. Calculated for C₂₀ H₂₈ N₂ O₆ Si: C,57.12; H,6.71; N,6.66. Found:C,57.28; H,6.75; N,6.60.

EXAMPLE 31 4-[3-(P-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one##STR92##

A solution ofN-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one(5.17 g, 12.3 mMol) in methanol (55 ml) is treated with 1N hydrochloricacid (6.2 ml) and then kept at room temperature for 200 mins. Thesolution is treated with 1M dipotassium hydrogenphosphate (6.2 ml) andconcentrated under vacuum. The residue is taken up in ethyl acetate (100ml), washed with brine, dried over magnesium sulfate, filtered, andevaporated under vacuum. Triturating the resulting oil with diethylether yields 4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one(3.42 g, 91%) as an off-white powder: mp 50°-52°; IR (CH₂ Cl₂) 3416,1767, 1723, 1528, and 1352 cm⁻¹ ; NMR (CDCl₃) α2.60 (ddd,1,J=1,2.7, and15.1,H3β), 2.77 (dd,1,J=8.4 and 18.2, CHCH₂ CO), 3.13 (dd,1,J=5.1 and18.2, CHCH₂ CO), 3.20 (ddd,1,J=2.4, 5.0, and 15.1, H3α), 3.57 (s,2,COCH₂CO₂), 3.98 (m,1,H4); 5.27 (s,2,CH₂ Ar), 6.28 br s,1,NH), 7.53 and 8.23(two d's,4,J=8.5, ArH); mass spectrum m/e 306(M+), 264(M+-42), 237, 153,125, 111, and 136.

EXAMPLE 324-[3-(P-nitrobenzylorycarbonyl)-3-diazo-2-oxopropyl]-azetidin-2-one##STR93##

p-Carboxybenzyenesulfonylazide (2.67 g, 11.8 mMol) and triethylamine(4.68 ml, 33.6 mMol) are added to an ice-cold, stirring solution of4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (3.42 g,11.2 mMol) in anhydrous acetonitrile (70 ml). The resulting mixture isstirred in the cold for 10 minutes and at room temperature for 60minutes. The mixture is diluted with ethyl acetate (200 ml) andfiltered. The filtrate is washed with water (2×100 ml), 1M pH 3phosphate buffer (50 ml), 0.1M pH 7 phosphate buffer (100 ml), andbrine, dried over magnesium sulfate, filtered, and evaporated undervacuum to a yellow foam (3.75 g). The crude product is taken up inmethylene chloride (ca. 10 ml), heated briefly with activated charcoal,and filtered through a pad of magnesium sulfate. The filtrate is dilutedwith diethyl ether (ca. 40 ml) and scratched to yield a precipitate. Theprecipitate is collected, washed with ether, and dried under vacuum toprovide4-[3-(p-nitrobenzyloxycarbonyl)-3-diazo-2-oxopropyl]-azetidin-2-one(3.29 g, 88%) as a pale yellow powder: mp 114.5°-116.6°; IR (CH₂ Cl₂)3413, 2142, 1767, 1724, 1657, 1530, and 1352 cm⁻¹ ; NMR (CDCl₃) α2.68(ddd,1,J=1.2, 2.7, and 14.8, H3β), 3.02 (dd,1,J=8.4 and 18.0, CHCH₂ CO),3.22 (ddd,1,J=2.4, 4.8, and 14.8, H3α); 343 (dd,1,J=4.6 and 18.0, CHCH₂CO), 4.00 (m,1,H4), 5.38 (s,2,CH₂ Ar), 6.30 (brs,1,NH), 7.57 and 8.27(two d's,4, J=8.5, ArH); mass spectrum m/e 332(M+), 304(M+-28),290(M+-42), 262, and 263.

Anal., calculated for C₁₄ H₁₂ N₄ O₆ : C,50.61; H,3.64; N,16.86. Found:C,50.34; H,3.42; N,16.72.

EXAMPLE 33 P-nitrobenzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate ##STR94##

A suspension of4-[3-(p-nitrobenzylocycarbonyl)-3-diazo-2-oxopropyl]-azetidin-2-one(2.93g) and rhodium (II) acetate (15 mg) in anhydrous toluene (300 ml) isdegassed by bubbling nitrogen through it for 60 minutes. The mixture isthen stirred and heated in an oil bath maintained at 80° C. After a fewminutes, the diazo compound dissolves and gas evolution commences. Themixture is heated at 80° C. for 100 minutes, then allowed to stand atroom temperature for 30 mins. before filtering through a pad of celite.The filtrate is evaporated under vacuum to an oily residue which istriturated with diethyl ether to afford p-nitrobenzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (2.53 g, 94%) as anoff-white powder. Recrystallization from ether provides analyticallypure product: mp 127°-128°: IR (CH₂ Cl₂) 1776, 1753, 1529, and 1352 cm⁻¹; NMR (CDCl₃) α 2.47 (dd,1,J=8.2 and 18.8, H4a), 2.98 (dd,1,J=6.8 and18.8, H4b), 3.00 (dd,1,J=2.0 and 12.0, H6β), 3.70 (dd,1,J=4.8 and 12.0,H6α), 4.20 (m,1,H5), 4.80 (s,1,H2), 5.32 (s,2,CH₂ Ar), 7.57 and 8.25(two d's,4, J=8,ArH); mass spectrum m/e 304(M+), 276(M+-28), 262(M+-42), and 168(M+-136).

Anal., calculated for C₁₄ H₁₂ N₂ 06: C,55.27; H,3.98; N,9.21. Found:C,55.06; H,4.03; N,8.99.

EXAMPLE 34 P-nitrobenzyl3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate##STR95##

p-toluenesulfonic anhydride (520 mg, 1.59 mμol) andN,N-diisopropylethylamine (300 μl, 1.72 mμol) are added to an ice-cold,stirring solution of p-nitrobenzyl1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (484 mg, 1.59 mμol) inanhydrous methylene chloride (17 ml). The resulting solution is stirredin the cold for 2 hours, then diluted with more methylene chloride,washed with water, 1μ ph 3.4 phosphate buffer and saturated aqueoussodium bicarbonate, dried with magnesium sulfate, filtered, andevaporated under vacuum. Addition of cold ethyl acetate and a few seedcrystals to the oily residue induces crystallization. The product iscollected, washed with cold ethyl acetate and dried under vacuum toafford p-nitrobenzyl3-(p-toluenesulfonyloxy)-1-azabicyclo[3.200]hept-2-en-7-one-2-carboxylate(466 mg, 61%) as off-white crystals: mp 99°-102° (dec.); IR (neat) 1790,1725, 1521, 1345, and 1172 cm⁻¹ ; UV (CH₂ Cl₂) 272 nm; NMR (CDCl₃) 82.40 (s,3,ArCH₃), 3.06 (dd,1,J=3.0 and 17.2, HGβ), 3.16 (dd,1,J=9.0 and9.0,H4a), 3.31 (dd,1,J=9.0 and 10.0, H46), 3.59 (dd,1,J=5.8 and 17.2,HG), 4.24 (m,1,H5), 5.20 and 5.32 (ABq,2,J=14.0,CH₂ Ar), 7.32 and 7.77(two d's,4,J=8.0, p-MeC₆ H₄), 7.51 and 8.19 (two d's,4,J=8.0,p-NO₂ C₆H₄).

EXAMPLE 35 Benzyl3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate ##STR96##

A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate(25.9 mg, 0.1 mMol) in anhydrous hexamethylphosphoramide (1.0 ml) iscooled in an ice-bath and stirred under a nitrogen atmosphere. Dimethylsulfate (11.4 μl, 0.12 mMol) and 57% sodium hydride in mineral oil (5.0mg, 0.12 mMol) are added to the solution. The cooling bath is removedand the resulting mixture is stirred at room temperature for 60 minutes.The mixture is diluted with ethyl acetate (10 ml) and water (20 ml),shaken, and the layers separated. The organic layer is washed with water(3×5 ml) and brine, dried with magnesium sulfate, diluted with toluene(10 ml), and evaporated under vacuum to an oil. This material ischromatographed on a 0.25 mm×10×20 cm silica gel GF plate using 3:1toluene-ethyl acetate as developing solvent. The major UV visible bandat R_(f) 0.1 was removed and eluted with ethyl acetate to provide benzyl3 -methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (5.6 mg) asa clear oil: IR (CH₂ Cl₂) 1775 and 1700 cm⁻¹ ; UV (EtOAc) 288 nm; NMR(CDcl₃) δ2.87 (dd, 1, J=2.8 and 16, H6β), 3.03 (m, 2, H4a and H4b), 3.50(dd, 1, J=5.5 and 16, H6α), 3.80 (m, 1, H5), 3.92 (s, 3, CH₃), 5.28 (s,2, CH₂ φ), and 7.40 (m, 5, C₆ H₅); mass spectrum m/e 23 (m+) and 231(M+-42).

This product is also obtained by treating the bicyclo keto ester withdimethyl sulfate and excess potassium carbonate inhexamethylphosphoramide or dimethylformamide.

EXAMPLE 36 Preparation of Pharmaceutical Compositions

One such unit dosage form comprises 120 mg of6-(3-phenyl-1-hydroxypropyl)-3-[N-methyl-N-(2-dimethylaminoethyl)amino]-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylicacid with 20 mg of lactose and 5 mg of magnesium stearate and placingthe 145 mg mixture into a No. 3 gelatin capsule. Similarly, by employingmore of the active ingredient and less lactose, other dosage forms canbe put up in No. 3 gelatin capsules and should it be necessary to mixmore than 145 mg of ingredients together, larger capsules such ascompressed tablets and pills can also be prepared. The followingexamples are illustrative of the preparation of pharmaceuticalformulations:

    ______________________________________                                        TABLET                PER TABLET                                              ______________________________________                                        6-(3-phenyl-1-hydroxypropyl)-3-[N--                                                                 125 mg.                                                 methyl-N--(2-dimethylaminoethyl)amino]-                                       1-azabicyclo[3 · 2 · 0]hept-2-en-7-one-2-                   carboxylic acid                                                               Cornstarch, U.S.P.     6 mg.                                                  Dicalcium Phosphate   192 mg.                                                 Lactose, U.S.P.       190 mg.                                                 ______________________________________                                    

The active ingredient is blended with the dicalcium phosphate, lactoseand about half of the cornstarch. The mixture is then granulated with a15% cornstarch paste (6 mg) and rough-screened. It is dried at 45° C.and screened again through No. 16 screens. The balance of the cornstarchand the magnesium stearate is added and the mixture is compressed intotablets, approximately 0.5 inch, in diameter each weighing 800 mg.

    ______________________________________                                        PARENTERAL SOLUTION                                                           Ampoule:                                                                      6-(3-phenyl-1-hydroxypropyl)-3-[N--                                                                    500    mg.                                           methyl-N--(2-dimethylaminoethyl)amino]-                                       1-azabicyclo[3 · 2 · 0]hept-2-en-7-one-2-                   carboxylic acid                                                               OPTHALMIC SOLUTION                                                            6-(3-phenyl-1-hydroxypropyl)-3-[N--                                                                    100    mg.                                           methyl-N--(2-dimethylaminoethyl)amino]-                                       1-azabicyclo[3 · 2 · 0]hept-2-en-7-one-                     2-carboxylic acid                                                             Hydroxypropylmethyl      5      mg.                                           Sterile Water to         1      ml.                                           OTIC SOLUTION                                                                 6-(3-phenyl-1-hydroxypropyl)-3-[N--                                                                    100    mg.                                           methyl-N--(2-dimethylaminoethyl)amino]-                                       1-azabicyclo[3 · 2 · 0]hept-2-en-7-one-                     2-carboxylic acid                                                             Benzalkonium chloride    0.1    mg.                                           Sterile Water to         1      ml.                                           TOPICAL OINTMENT                                                              6-(3-phenyl-1-hydroxypropyl)-3-[N--                                                                    100    mg.                                           methyl-N--(2-dimethylaminoethyl)amino]-                                       1-azabicyclo[3 · 2 · 0]hept-2-en-7-one                      2-carboxylic acid                                                             Polyethylene Glycol 4000 U.S.P.                                                                        400    mg.                                           Polyethylene Glycol 400 U.S.P.                                                                         1.0    gram                                          ______________________________________                                    

The active ingredient in the above formulations may be administeredalone or in combination with other biologically active ingredients, asfor example, with other antibacterial agents such as lincomycin, apenicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin,and kanamycin, or with other therapeutic agents such as probenecid.

What is claimed is:
 1. A compound having the structural formula:##STR97## and the pharmaceutically acceptable salts, thereof, wherein:R' and R" are independently selected from the group consisting ofhydrogen, substituted with 1-3 substituents and unsubstituted: alkyl andcycloalkyl having 1-10 carbon atoms, phenylalkyl and heterocyclylalkylwherein the alkyl moiety has 1-6 carbon atoms and the heterocyclyl isselected from ##STR98## wherein the ring or chain substituent orsubstituents on R', R", or the cyclic radical formed by their joinderare selected from amino, mono- or di-alkylamino (each alkyl having 1-6carbon atoms), hydroxyl, carboxyl, alkoxyl having 1-6 carbon atoms,chloro, bromo, fluoro, nitro, sulfamoyl, phenyl, benzyl, andalkoxycarbonyl having 1-3 carbon atoms in the alkoxyl moiety; and R¹ andR² are independently selected from the group consisting of hydrogen,substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl,having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms inthe alkyl moieties; phenyl; aralkyl, aralkenyl, and aralkynyl whereinthe aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms;wherein the substituent or substituents relative to the above-namedradicals are selected from the group consisting of: amino, mono- ordi-alkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio,sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano andcarboxy; and wherein the alkyl moieties of the above-recitedsubstituents have 1-6 carbon atoms; when R¹ /R² is hydrogen, R² /R¹ isnot 1-hydroxyethyl.
 2. A compound according to claim 1 wherein R¹ ishydrogen, methyl, or methoxyl and R² is selected from: ##STR99##
 3. Anantibacterial pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 1 and a pharmaceuticalcarrier therefor.
 4. A compound having the structural formula:##STR100## and the pharmaceutically acceptable salts thereof, wherein:R¹ is hydrogen, methyl, or methoxyl and R² is selected from: ##STR101##and wherein the 3-substituent --NR'R" is selected from the groupconsisting of: ##STR102##